Owing to the Western dietary lifestyle and chronic lack of exercise, approximately three hundred million people around the world suffer from type II diabetes mellitus, which is characterized by hyperglycemia resulting from excessive hepatic glucose production and peripheral insulin resistance, and the number of diabetic patients is increasing. Dietary and exercise therapies are essential for treatment of diabetes, but insulin or several oral antidiabetic agents are further used when these therapies do not sufficiently control the patients' symptoms.
In recent years, a biguanide compound, a sulfonylurea compound, an insulin resistance modifier, and an α-glucosidase inhibitor have been used as antidiabetic agents, but these antidiabetic agents have several side effects. For example, the biguanide compound causes lactic acidosis, the sulfonylurea compound causes severe hypoglycemia, the insulin resistance modifier causes swelling and heart failure, and the α-glucosidase inhibitor causes abdominal distention and diarrhea. Under such situations, there is a need for development of novel drugs that are able to treat diabetes without causing the above-described side effects.
In recent years, the glucose toxicity theory in which hyperglycemia is associated with the onset of diabetes, and progressive disorders such as diabetic complications has been reported. That is, chronic hyperglycemia causes a decrease in insulin secretion and a reduction in insulin sensitivity, resulting in self-worsening diabetes due to an increase in blood glucose concentration [see Diabetologia (1985) 28, p. 119; and Diabetes Care (1990) 13, p. 610]. Therefore, hyperglycemia may be treated to stop the above-described self-worsening cycle, thereby treating or preventing diabetes.
As one method of treating hyperglycemia, a method of directly secreting an excessive amount of glucose in urine so that the blood glucose concentration decreases to a normal range may be contemplated. For example, when the sodium-glucose linked transporters (SGLTs) present in proximal convoluted tubules of the kidney are inhibited, the glucose reuptake in the kidney is inhibited, and thus, the secretion of glucose in the urine is stimulated, resulting in a decrease in the blood glucose concentration. In fact, it was confirmed that, when phlorizin having an SGLT inhibitory activity is subcutaneously administered continuously in a diabetic animal model, hyperglycemia may return to a normal state, and a blood glucose level may be maintained for a long period of time in a normal range, resulting in an increase in insulin secretion and improvement of insulin tolerance [see Journal of Clinical Investigation (1987) 79, p. 1510; ibid. p. 1037; ibid. p. 561].
Also, while a diabetic animal model is treated with the SGLT inhibitor for a long period of time, the SGLT inhibitor does not cause side effects in the kidney of the animal and a response of increased insulin secretion and improved insulin sensitivity is exhibited without causing any imbalance in the level of electrolytes in the blood. As a result, the onset and progression of diabetic nephropathy and neuropathy are prevented [see Journal of Medicinal Chemistry (1999) 42, p 5311; and British Journal of Pharmacology (2001) 132, p. 578].
Accordingly, it can be expected from the above-described results that the SGLT inhibitor increases insulin secretion and improves insulin tolerance by reducing a blood glucose level in diabetic patients, and also prevents the onset and progression of diabetes and diabetic complications.